There are currently no drugs that reverse or halt the progression of Huntington's disease (HD). Moreover, drug candidates against a single molecular target have failed. Therefore, a different approach to HD drug discovery is needed. Herein the hypothesis is tested that a compound that modulates a large set of HD-related targets will be effective against the disease. The rare flavonol fisetin induces transcription factors for neuroprotective and antioxidant genes, maintains ATP levels in stressed nerve cells, enhances the removal of intracellular aggregated proteins and is a potent anti-inflammatory compound. Fisetin has proven efficacy in mouse and fly models of Huntington's (Hum. Mol. Gen. 20:261, 2011). It is also effective in animal models of Alzheimer's disease, ischemic stroke, and the CNS complications of diabetes, all of which share some pathological features with HD. Potent derivatives of fisetin with improved pharmacology were made that maintain its multiple biological activities (J. Med. Chem. 55:378, 2012). From 150 synthetic fisetin derivatives, one has been selected for further study in the context of HD based on pharmacological parameters and the prevention of HD neurotoxicities in vitro. CMS121 is effective in eleven in vitro models that define most of the known brain toxicities associated with HD as well as in two different mouse models of AD. In addition, CMS121 has excellent ADME, safety, and pharmacological properties. Funds are independently being sought for Investigational New Drug (IND) toxicology studies for the use of CMS-121 for the treatment of AD. If it were possible to demonstrate therapeutic efficacy in HD mouse models, then CMS- 121 could be sped to the clinic for the treatment of HD. Therefore, the two Specific Aims of this application are to test the therapeutic efficacy of CMS121 in 4 well-established mouse models of HD and at the same time examine the striatal gene expression relationship between these models and drug effects. The R6/2 mice in which fisetin is effective will be used for initial dosing studies. These experiments will be followed by N171-82Q animals that have a slower disease onset and the YAC128 model that expresses full-length hHTT, have a normal life span, but exhibit motor defects at 6 mo and have more human-like pathology. Finally, a therapeutic study will be done in which the drug candidate is given to YAC128 mice that are symptomatic. Changes in striatal gene expression in each will be assayed to define the relationship between the four models and their drug responses. At the end of two years, CMS121 will have been tested in multiple rigorous animal models of HD and a greater understanding of the physiological relationship between these models will have been gained. This will provide an excellent test of an alternative approach to the current drug discovery paradigm for HD that is based on preselected single targets. Most importantly, because of its exceptional neuroprotective activities, good medical chemical properties, and the excellent safety profile, CMS121 will be a very strong clinical candidate for HD treatment.